CN109705121B - Preparation method of linagliptin intermediate - Google Patents
Preparation method of linagliptin intermediate Download PDFInfo
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Abstract
The invention provides a preparation method of a linagliptin intermediate (1- [ (4-methyl-quinazolin-2-yl) methyl ] -3-methyl-7- (2-butyn-1-yl) -8- [ (R) -3- (tert-butoxycarbonylamino) -piperidin-1-yl ] -2, 6-dione-2, 3,6, 7-tetrahydro-1H-purine) for treating type II diabetes, wherein 8-bromo-7- (2-butynyl) -3, 7-dihydro-3-methyl-1H-purine-2, 6-dione and 2-chloromethyl-4-methyl quinazoline are reacted in an organic solvent in the presence of potassium carbonate and PEG, adding (R) -3-tert-butyloxycarbonylaminopiperidine into the reaction mixture, completing the reaction, preparing the intermediate compound, improving the yield and purity, shortening the reaction period, reducing the production cost and providing guarantee for finally obtaining the high-purity linagliptin.
Description
Technical Field
The invention belongs to the field of chemical pharmacy, and particularly relates to a preparation process of a hypoglycemic drug linagliptin intermediate.
Technical Field
Linagliptin (English name is Linagliptin) has a chemical name of [ (3R) -3-amino-1-piperidyl ] -7- (2-butynyl) -3, 7-dihydro-3-methyl-1- [ (4-methyl-2-quinazolinyl) methyl ] -1H-purine-2, 6-dione. Linagliptin is an 8- (3-aminopiperidine) -xanthine derivative WO 2004018468 developed by the company brigling invagrehn, germany; the dipeptidyl peptidase-4 (DPP-4) inhibitor is a very active dipeptidyl peptidase-4 (DPP-4) inhibitor, has the characteristics of high selectivity, long acting and oral effectiveness, and simultaneously has good safety and tolerance, is approved by the FDA in the United states and marketed in 5 months of 2011, is used for treating type 2 diabetes, and can improve the blood sugar control level of type 2 diabetes (T2DM) adult patients on the basis of diet control and physical exercise. Linagliptin has excellent renal safety relative to other gliptin drugs. It does not need to adjust dosage for patients with renal function impairment or the elderly with the age of more than 75 years, thereby greatly expanding the range of drug-taking population and improving the drug-taking compliance of patients.
At present, the synthesis of linagliptin mainly uses 3-methyl-8-halogenated xanthine as a basic parent nucleus, and is characterized in that a 9-site nitrogen atom is sequentially connected with a butynyl group to prepare a linagliptin intermediate of a compound II, a 1-site nitrogen atom is connected with a quinazoline ring, and an 8-site carbon atom is connected with (R) -3-aminopiperidine. The processes disclosed in the prior art generally employ a reaction of a halogenated quinazoline group-containing compound with a halogenated purine derivative, isolation of the intermediate compound (8-bromo-7- (2-butynyl) -3, 7-dihydro-3-methyl-1- [ (4-methyl-2-quinazolinyl) methyl ] -1H-purine-2, 6-dione) and reaction with a group-protected piperidine derivative to give the intermediate (1- [ (4-methyl-quinazolin-2-yl) methyl ] -3-methyl-7- (2-butyn-1-yl) -8- [ (R) -3- (tert-butoxycarbonylamino) -piperidin-1-yl ] -2, 6-diketone-2, 3,6, 7-tetrahydro-1H-purine), and then removing a protecting group to obtain a final product linagliptin.
The preparation processes all have the problems of complex production process, low purity of intermediates and products, difficult subsequent purification process, increased production cost and the like, and limit the industrial production of the medicine. Due to the technical difficulties in the prior art, a new industrial production method of linagliptin needs to be found.
Disclosure of Invention
In order to solve the technical problem of preparation of the linagliptin intermediate, the invention provides a preparation method of a linagliptin intermediate (1- [ (4-methyl-quinazolin-2-yl) methyl ] -3-methyl-7- (2-butyn-1-yl) -8- [ (R) -3- (tert-butoxycarbonylamino) -piperidin-1-yl ] -2, 6-dione-2, 3,6, 7-tetrahydro-1H-purine).
The invention provides a preparation method of a linagliptin intermediate, which comprises the following steps:
(1) in the presence of potassium carbonate and PEG, 8-bromo-7- (2-butynyl) -3, 7-dihydro-3-methyl-1H-purine-2, 6-dione and 2-chloromethyl-4-methyl quinazoline react in an organic solvent to obtain a reaction mixed solution; (2) (R) -3-tert-Butoxycarbonylaminopiperidine was added to the above reaction mixture, and the reaction was completed to prepare 1- [ (4-methyl-quinazolin-2-yl) methyl ] -3-methyl-7- (2-butyn-1-yl) -8- [ (R) -3- (tert-butoxycarbonylamino) -piperidin-1-yl ] -2, 6-dione-2, 3,6, 7-tetrahydro-1H-purine as an intermediate compound.
In the preparation method of the linagliptin intermediate, the organic solvent is one or more selected from N, N-dimethylformamide, dimethyl sulfoxide, N-methylpyrrolidone, dichloromethane, toluene, methanol, ethanol, isopropanol, acetonitrile and tetrahydrofuran.
In the preparation method of the linagliptin intermediate, the PEG is selected from PEG400 and the like.
According to the preparation method of the linagliptin intermediate, in the step (1), the reaction temperature is 50-70 ℃, and the reaction time is 2-10 hours.
According to the preparation method of the linagliptin intermediate, in the step (2), the reaction temperature is 50-70 ℃, and the reaction time is 4-12 hours.
In the preparation method of the linagliptin intermediate, the feeding molar ratio of the 8-bromo-7- (2-butynyl) -3, 7-dihydro-3-methyl-1H-purine-2, 6-dione, the 2-chloromethyl-4-methyl quinazoline and the (R) -3-tert-butoxycarbonylaminopiperidine is 1.0:1.0-2.0: 1.0-2.0.
In the preparation method of the linagliptin intermediate, the feeding ratio of the 8-bromo-7- (2-butynyl) -3, 7-dihydro-3-methyl-1H-purine-2, 6-dione, the 2-chloromethyl-4-methyl quinazoline and the (R) -3-tert-butoxycarbonylaminopiperidine is 1.0:1.0-1.5:1.0-1.5, preferably 1.0:1.1-1.2: 1.1-1.2.
In the preparation method of the linagliptin intermediate, the feeding ratio of 8-bromo-7- (2-butynyl) -3, 7-dihydro-3-methyl-1H-purine-2, 6-dione to PEG is 0.1 mol: 1-5ml, preferably 0.1 mol: 2-3 ml.
According to the preparation method of the linagliptin intermediate, the organic solvent is selected from a mixed solution of N-methyl-2-pyrrolidone and acetonitrile, and the volume ratio of the N-methyl-2-pyrrolidone to the acetonitrile is 2:1.
In the preparation method of the linagliptin intermediate, the intermediate compound 1- [ (4-methyl-quinazolin-2-yl) methyl ] -3-methyl-7- (2-butyn-1-yl) -8- [ (R) -3- (tert-butoxycarbonylamino) -piperidin-1-yl ] -2, 6-dione-2, 3,6, 7-tetrahydro-1H-purine is deprotected to obtain linagliptin.
In the preparation method of the linagliptin intermediate, the intermediate compound 1- [ (4-methyl-quinazolin-2-yl) methyl ] -3-methyl-7- (2-butyn-1-yl) -8- [ (R) -3- (tert-butoxycarbonylamino) -piperidin-1-yl ] -2, 6-dione-2, 3,6, 7-tetrahydro-1H-purine is refined by dichloromethane and n-hexane, then is deprotected by trifluoroacetic acid, and absolute ethanol and methyl tert-butyl ether are refined to obtain linagliptin.
The preparation method has the beneficial effects that the yield and the purity of the intermediate compound are improved; the reaction period is shortened, the production cost is reduced, and the guarantee is provided for finally obtaining the high-purity linagliptin.
Detailed Description
In order to better understand the present invention, the following examples are included to further illustrate the present invention. However, the present invention is not limited to the following examples.
Example 1
Adding 100mmol of 8-bromo-7- (2-butynyl) -3, 7-dihydro-3-methyl-1H-purine-2, 6-dione and 120mmol of 2-chloromethyl-4-methyl quinazoline into 300mL of N-methylpyrrolidone, adding 200mmol of potassium carbonate and 120.5 mL of PEG4002, stirring at 50 ℃ for reaction for 5 hours to obtain a reaction mixed solution, adding 120mmol of (R) -3-tert-butoxycarbonylaminopiperidine into the reaction mixture without separation, stirring at 60 ℃ for reaction for 8 hours to complete the reaction, adding 500mL of water into the reaction solution to precipitate a solid, filtering, dissolving a wet filter cake with dichloromethane, washing with water, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, adding N-hexane to precipitate a solid, filtering, and drying to obtain the linagliptin intermediate 1- [ (4-methyl-quinazolin-2-yl) methyl ] -3-methyl-7- (2-butyn-1-yl) -8- [ (R) -3- (tert-butoxycarbonylamino) -piperidin-1-yl ] -2, 6-dione-2, 3,6, 7-tetrahydro-1H-purine in 93.3% yield and 99.5% purity.
Example 2
Adding 100mmol of 8-bromo-7- (2-butynyl) -3, 7-dihydro-3-methyl-1H-purine-2, 6-dione and 120mmol of 2-chloromethyl-4-methyl quinazoline into 200mL of N-methylpyrrolidone and 100mL of acetonitrile, adding 200mmol of potassium carbonate and 100.5 mL of PEG4002, stirring and reacting at 50 ℃ for 6 hours to obtain a reaction mixed solution, adding 120mmol of (R) -3-tert-butoxycarbonylaminopiperidine into the reaction mixture without separation, stirring and reacting at 60 ℃ for 8 hours to complete the reaction, adding 500mL of water into the reaction solution to precipitate a solid, filtering, dissolving a wet filter cake with dichloromethane, washing with water, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, adding N-hexane to precipitate a solid, filtering, and drying to obtain the linagliptin intermediate 1- [ (4-methyl-quinazolin-2-yl) ) Methyl ] -3-methyl-7- (2-butyn-1-yl) -8- [ (R) -3- (tert-butoxycarbonylamino) -piperidin-1-yl ] -2, 6-dione-2, 3,6, 7-tetrahydro-1H-purine in 95.1% yield and 99.4% purity.
Example 3
Adding 100mmol of 8-bromo-7- (2-butynyl) -3, 7-dihydro-3-methyl-1H-purine-2, 6-dione and 120mmol of 2-chloromethyl-4-methyl quinazoline into 300mL of N-methylpyrrolidone, adding 200mmol of potassium carbonate and 200mL of PEG4001.5 mL of potassium carbonate, stirring at 60 ℃ for reaction for 8 hours to obtain a reaction mixed solution, adding 120mmol of (R) -3-tert-butoxycarbonylaminopiperidine into the reaction mixture without separation, stirring at 60 ℃ for reaction for 8 hours to complete the reaction, adding 500mL of water into the reaction solution to precipitate a solid, filtering, dissolving a wet filter cake with dichloromethane, washing with water, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, adding N-hexane to precipitate a solid, filtering, and drying to obtain a linagliptin intermediate 1- [ (4-methyl-quinazolin-2-yl) methyl ] -3-methyl-7- (2-butyn-1-yl) -8- [ (R) -3- (tert-butoxycarbonylamino) -piperidin-1-yl ] -2, 6-dione-2, 3,6, 7-tetrahydro-1H-purine in 89.6% yield and 99.2% purity.
Example 4
Adding 100mmol of 8-bromo-7- (2-butynyl) -3, 7-dihydro-3-methyl-1H-purine-2, 6-dione and 150mmol of 2-chloromethyl-4-methyl quinazoline into 300mL of N-methylpyrrolidone, adding 200mmol of potassium carbonate and 150.5 mL of PEG4002, stirring at 50 ℃ for reaction for 6 hours to obtain a reaction mixed solution, adding 150mmol of (R) -3-tert-butoxycarbonylaminopiperidine into the reaction mixture without separation, stirring at 60 ℃ for reaction for 8 hours to complete the reaction, adding 500mL of water into the reaction solution to precipitate a solid, filtering, dissolving a wet filter cake with dichloromethane, washing with water, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, adding N-hexane to precipitate a solid, filtering, and drying to obtain the linagliptin intermediate 1- [ (4-methyl-quinazolin-2-yl) methyl ] -3-methyl-7- (2-butyn-1-yl) -8- [ (R) -3- (tert-butoxycarbonylamino) -piperidin-1-yl ] -2, 6-dione-2, 3,6, 7-tetrahydro-1H-purine in 93.6% yield and 99.4% purity.
Example 5
Adding 100mmol of 8-bromo-7- (2-butynyl) -3, 7-dihydro-3-methyl-1H-purine-2, 6-dione and 120mmol of 2-chloromethyl-4-methyl quinazoline into 300mL of DMF, adding 200mmol of potassium carbonate and PEG 4003 mL, stirring at 50 ℃ for 5 hours to react to obtain a reaction mixed solution, adding 120mmol of (R) -3-tert-butoxycarbonylaminopiperidine into the reaction mixture without separation, stirring at 60 ℃ for 8 hours to react, adding 500mL of water into the reaction solution to precipitate a solid, filtering, dissolving a wet filter cake with dichloromethane, washing with anhydrous sodium sulfate, drying, filtering, concentrating under reduced pressure, adding n-hexane, precipitating a solid, filtering, and drying to obtain a linagliptin intermediate 1- [ (4-methyl-quinazolin-2-yl) methyl ] -3-methyl intermediate -7- (2-butyn-1-yl) -8- [ (R) -3- (tert-butoxycarbonylamino) -piperidin-1-yl ] -2, 6-dione-2, 3,6, 7-tetrahydro-1H-purine in 92.8% yield and 99.2% purity.
By the preparation method, the yield and the purity of the preparation process of the intermediate compound 1- [ (4-methyl-quinazoline-2-yl) methyl ] -3-methyl-7- (2-butyn-1-yl) -8- [ (R) -3- (tert-butyloxycarbonylamino) -piperidine-1-yl ] -2, 6-diketone-2, 3,6, 7-tetrahydro-1H-purine are improved; the reaction period is shortened, the production cost is reduced, the guarantee is provided for finally obtaining the high-purity linagliptin, and the method has important technical significance and application value.
The use of the above examples is merely illustrative of the present invention and is not intended to limit the scope of the present invention. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (3)
1. A preparation method of a linagliptin intermediate comprises the following steps:
adding 100mmol of 8-bromo-7- (2-butynyl) -3, 7-dihydro-3-methyl-1H-purine-2, 6-dione and 120mmol of 2-chloromethyl-4-methyl quinazoline into 200mL of N-methylpyrrolidone and 100mL of acetonitrile, adding 200mmol of potassium carbonate and 100.5 mL of PEG4002, stirring and reacting at 50 ℃ for 6 hours to obtain a reaction mixed solution, adding 120mmol of (R) -3-tert-butoxycarbonylaminopiperidine into the reaction mixture without separation, stirring and reacting at 60 ℃ for 8 hours to complete the reaction, adding 500mL of water into the reaction solution to precipitate a solid, filtering, dissolving a wet filter cake with dichloromethane, washing with water, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, adding N-hexane to precipitate a solid, filtering, and drying to obtain the linagliptin intermediate 1- [ (4-methyl-quinazolin-2-yl) ) Methyl ] -3-methyl-7- (2-butyn-1-yl) -8- [ (R) -3- (tert-butoxycarbonylamino) -piperidin-1-yl ] -2, 6-dione-2, 3,6, 7-tetrahydro-1H-purine.
2. The method for preparing linagliptin intermediate according to claim 1, further comprising the step of deprotecting 1- [ (4-methyl-quinazolin-2-yl) methyl ] -3-methyl-7- (2-butyn-1-yl) -8- [ (R) -3- (tert-butoxycarbonylamino) -piperidin-1-yl ] -2, 6-dione-2, 3,6, 7-tetrahydro-1H-purine, which is an intermediate compound, to obtain linagliptin.
3. The method for producing a linagliptin intermediate according to claim 1, further comprising a step of refining 1- [ (4-methyl-quinazolin-2-yl) methyl ] -3-methyl-7- (2-butyn-1-yl) -8- [ (R) -3- (tert-butoxycarbonylamino) -piperidin-1-yl ] -2, 6-dione-2, 3,6, 7-tetrahydro-1H-purine with dichloromethane and n-hexane, deprotecting with trifluoroacetic acid, and refining with anhydrous ethanol and methyl tert-butyl ether to obtain linagliptin.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103319483A (en) * | 2012-10-19 | 2013-09-25 | 药源药物化学（上海）有限公司 | Preparation method of important intermediate of linagliptin |
| CN104387390A (en) * | 2014-11-04 | 2015-03-04 | 广东东阳光药业有限公司 | Method for preparing purine derivatives |
| WO2015087240A1 (en) * | 2013-12-11 | 2015-06-18 | Ranbaxy Laboratories Limited | Process for the preparation of linagliptin and an intermediate thereof |
| CN105622609A (en) * | 2016-03-10 | 2016-06-01 | 上海万代制药有限公司 | Preparation method for linagliptin |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103319483A (en) * | 2012-10-19 | 2013-09-25 | 药源药物化学（上海）有限公司 | Preparation method of important intermediate of linagliptin |
| WO2015087240A1 (en) * | 2013-12-11 | 2015-06-18 | Ranbaxy Laboratories Limited | Process for the preparation of linagliptin and an intermediate thereof |
| CN104387390A (en) * | 2014-11-04 | 2015-03-04 | 广东东阳光药业有限公司 | Method for preparing purine derivatives |
| CN105622609A (en) * | 2016-03-10 | 2016-06-01 | 上海万代制药有限公司 | Preparation method for linagliptin |
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